The amyloid p-protein (Afi) is closely linked to the pathophysiological processes that lead to Alzheimer disease (AD), and likely are ultimately responsible for the neural system collapse that causes the clinical syndrome of dementia. However the mechanistic role of Afi and the form in which it is toxic remain controversial. One hypothesis is that the insoluble amyloid plaque itself is deleterious to the brain. Contrasting this argument is the hypothesis that the damage is caused by soluble Aft oligomers. The overall goal of his Project is to examine these two competing hypotheses critically and determine whether one or both are more likely. In this research plan, we propose three specific aims built around advances in biochemical and morphological techniques. To learn whether and how soluble A(3oligomers, monomers and/or plaque cores correlate with the histopathological changes (gliosis, Ap deposits, neurofibrillary tangles), we will quantify the levels of soluble oligomers and monomers by new Size Exclusion Chromatography and sensitive IP/Western techniques and correlate these findings with each subject's detailed neuropathological phenotype and with clinical information. A second approach to these questions will utilize a newly developed histological preparation that allows visualization of individual synaptic elements, fibrillar Ap, and oligomeric Ap simultaneously. We have observed that oligomeric Ap-directed antibodies reveal a "halo" around plaques that corresponds to the region around plaques that have diminished dendritic spine density. Furthermore, oligomeric Ap-directed antibodies demonstrate puncta that co-localize with PSD95 positive dendritic spines. These observations motivate an analysis of oligomeric Apand synaptic change that will take aim at fundamental mechanisms of Ap-associated synaptic loss. These studies will address a central unresolved question: how do soluble oligomeric forms relate to the fibrillar, histologically detected forms of Ap. Moreover, our experiments will also directly address whether Ap in cognitively normal controls who have Ap deposits differ from those in subjects with AD. By taking advantage of well characterized material from the MADRC Neuropathology Core's Brain Bank, Clinical Core evaluations, and Statistical Core expertise, we plan to test hypotheses directed at the relationship of Ap to cognitive impairment and neuronal toxicity. RELEVANCE (See instructions): Project 3 of the Massachusetts ADRC will test the competing hypotheses of the role of Ap protein and the form in which its toxicity is associated with cognitive dysfunction and Alzheimer's disease neuropathology.